1. Field of the Invention
The invention relates to an active substance-containing therapeutic system for application to the skin comprising at least two polymer-containing layers. The invention further relates to a manufacturing process as well as to a use of the therapeutic system.
2. Description of the Prior Art
The pharmaceutical preparation for delivery of active substances to the skin aims either at a transdermal systemic action or at a dermal, local action of the active substances released. Adherence to the application surface is secured through adhesives forming high-viscous, permanent-adhesive structures. Here, quality characteristics such as initial tackiness (tack), adhesive power (adhesion) and internal strength of the pressure-sensitive adhesive (cohesion) are distinguished.
The pharmaceutical preparation is an active substance-containing device which releases one or more medicinal agents at a predeterminable rate, continuously, over a defined period of time, to a defined site. Such a device is characterized by an exact plan of treatment, called dosage plan, and is called a therapeutic system (TS). As the systems according to the present invention are stuck to the skin as patches to obtain either a systemic or a local effect, these systems are referred to in the given context as transdermal therapeutic systems (TTSs) or as dermal therapeutic systems (DTSs).
The preparation according to the present invention has a high degree of efficacy. This means that the preparation leads to high bioavailability of the active substances. Action can be broken off at any time by the simple removal of the preparation. As a consequence, the preparation is characterized also by controllability of the active substance release. The preparation according to the invention furthermore has high reliability with regard to patients' observing the therapeutic plan (so-called compliance) since the frequency of application is greatly reduced as compared to conventional drug forms, and side effects occur only rarely. Further, the amount of active substance to be applied can, as a rule, be reduced. Thus, dose-dependent side effects are likewise reduced or avoided. This results in increased therapeutic safety.
Usually, an active substance-containing system, TTS or DTS, comprises an assembly of a plurality of layers comprising at least one active substance- and/or auxiliary substance-containing reservoir layer, a backing layer impermeable to the ingredients of the latter, and a protective layer to be removed prior to application to the skin.
The reservoir layer here consists as a rule of an amorphous polymer containing active substances and/or auxiliary substances. Apart from a number of advantageous properties of the polymer, especially with regard to its use as patches, such as diffusion-dependent absorption or release of the ingredients, or their flexibility in conforming to a given shape of the body at the application site, amorphous polymers on the other hand tend to show cold flow in the patch, especially in the case of prolonged storage, as a consequence of comparatively insufficient cohesion.
Whereas in pure-crystalline substances, at the melting point the molecular motion increases rapidly from a relatively low level to a high level with increasing temperature, amorphous polymers such as adhesives behave differently.
As the temperature increases, molecular movement increases in several reversible stages, mostly 5 different ones. In detail, five ranges of viscoelasticity are distinguished as glassy state (hard; lowest temperature), leathery state (turning point=glass transition temperature (Tg)=temperature at which a polymer changes from the solid glassy state to the rubber-elastic state), rubber-elastic state, rubber-elastic flow, and viscous state (highest temperature).
The transition from glassy state to the rubber-like state is accompanied by a marked change in the physical properties such as specific volume, modulus of elasticity, heat capacity, thermomechanic properties and refractive index. The melting point (Tm; solid and liquid polymer are balanced) of amorphous polymers is defined by partially crystalline polymer regions. Here, Tg is always below Tm.
Distinctions are made between:
Polymers which at room temperature (TA) are in the solid glassy state, with Tg, TM>Ta. Examples are isotactic polystyrene: Tg=85° C./Tm=240° C.; polyethylene terephthalate: Tg=69° C./Tm=265° C.; polyhexamethylene adipamide: Tg=53° C./Tm=265° C.; polytetrafluoroethylene: Tg=126° C./Tm=325° C.). Polymers which are in the soft rubberlike intermediate state (Tm>Ta>Tg). Examples are high-density polyethylene: Tg=−70° C./Tm=139° C.; isotactic polypropylene: Tg=−18° C./Tm=186° C. Polymers which are in the liquid viscous state (Ta>Tm, Tg; examples are polydimethyl siloxane: Tg=−121° C./Tm=−40° C.; 1,4-cis-polybutadiene: Tg=−95° C./Tm=2° C.).
It can be derived from this that the cohesion and thereby the cold flow of an adhesive having high-viscous, permanent-adhesive polymer structures is decisively influenced by the glass transition temperature of the polymers employed.
Cold flow describes a property of a material. The materials affected by this start to flow during storage without having been subjected to special influences, consequently they can be considered high-viscous liquids.
It is known from practice that TTSs and DTSs often tend to show cold flow. This leads to a patch becoming agglutinated with the primary packing means while it is being stored so that it can be removed subsequently only with difficulty. A further problem consists in that after application the patches leave black margins, residues of adhesive, on the surface of application which in part can be removed only by means of intensive cleaning measures.
WO 86/00814 as well as U.S. Pat. No. 5,186,938 describe the possibility of improving the cold flow in glycerol trinitrate-containing, self-adhesive, polyacrylic acid-derived polymers by crosslinking the polymers. For crosslinking, divalent metal ions or melamine are used, for example. This creates a coherent network that has a considerably lower tendency for cold flow than the starting polymer. Cross-linkage, which has a positive effect on cohesion, has, on the other hand, a negative influence on tack, which thereby deteriorates.
The latter is a universal rule of thumb. The inventors of the known method attempt to solve the problem by using the agent that brings about the cross linkage only in a relatively small amount in order to ensure a minimum tack. The problem with the procedure described by the inventors is that the degree of cross linkage must be adjusted accurately to guarantee optimum system properties.
To be independent from the sensitivity of cohesion and tack, which is dependent on the degree of cross link, a different procedure is proposed in EP 0 856 311 A1 and DE 197 06 824 C1. To improve the cohesion of the matrix without reducing the adhesive power on the skin, systems are proposed which consist of at least two layers. The special aspect here is that the layers although having the same polymer composition and the same concentration of dissolved ingredients, differ in the degree of cross linkage. While a layer with a lower degree of cross link ensures adhesion to the skin, another layer, having a higher cross link degree, reduces cold flow. Cross-linking is carried through in a known manner, for example, by addition of metallic ions or reactive reagents as well as by electron irradiation or irradiation with ultraviolet light.
Another possibility to improve cohesion is known from DE 40 20 144 C2. This document describes a possibility of improving cold flow without the use of reagents for cross-linking. To this end, a further non-adhesive but film-forming polymer is added to the self-adhesive base polymer. This film-forming polymer, which is typically characterized by a high molecular weight, results in a considerable improvement of cohesion.
The above-described processes for improving cohesion cannot be employed in all cases. For example, not all polymers which are adhesive and are thus suitable for the production of self-adhesive TTSs or DTSs can be crosslinked. Also, admixture of cohesion-enhancing polymers is not always possible, for reasons of compatibility.